This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and methods for treating cell proliferation-related disorders, cell death and apoptosis-related disorders.
Identification of therapeutic agents effective in the treatment of neoplastic diseases or for the treatment of neurological disorders is the subject of significant research efforts.
Protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function. A partial list of such kinases includes ab1, Akt, bcr-ab1, B1k, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDCFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. As such, inhibition of kinases has become an important therapeutic target.
Cell proliferation is the rapid reproduction of cells, such as by cell division. The cell cycle, which controls cell proliferation, is itself controlled by a family of serine-threonine kinases called cyclin dependent kinases (CDKs). The regulation of CDK activation is complex, and requires the association of the CDK with a member of the cyclin family of regulatory subunits. A further level of regulation occurs through both activating and inactivating phosphorylations of the CDK subunit. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/CDK activities. Loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer. (T. Noguchi et al., Am. J. Pathol., 156, 2135-47 (2000)) As such, inhibition of CDKs has become an important target in the study of chemotherapeutics (A. Senderowicz and E. Sausville, J. Nat. Canc. Instit., 92, 376-87 (2000)).
Kinases have also been implicated in diseases and disorders of the central nervous system. For example, patients suffering from stroke, Alzheimer""s disease or Parkinson""s disease would benefit from the inhibition of kinases. Cdk5 has been shown to be involved in Alzheimer""s pathology (R. Maccioni, et al., Eur. J. Biochem., 268, 1518-27 (2001)) and with neuronal development (G. Paglini and A. Caceres, Eur. J. Biochem., 268, 1528-33 (2001)).
Protein kinases also control programmed cell death, also known as apoptosis. Apoptosis is a ubiquitous physiological process used to eliminate damaged or unwanted cells in multicellular organisms. Disregulation of apoptosis is believed to be involved in the pathogenesis of many human diseases. The failure of apoptotic cell death has been implicated in various cancers, as well as autoimmune disorders. Conversely, increased apoptosis is associated with a variety of diseases involving cell loss such as neurodegenerative disorders and AIDS. As such, inhibition of apoptosis has become an important therapeutic target. Cdk5 has been shown to be involved in apoptosis pathology (A. Catania et al., Neuro-Oncology, 89-98 (April 2001)).
Quinolinones are known in the art. U.S. Pat. No. 4,127,574, issued Nov. 28, 1978, describes 3-sulfonyl-quinolinones as anti-allergic agents. U.S. Pat. No. 4,547,511, issued Oct. 15, 1985, describes 3-carboxamide-quinolinones as pharmaceuticals. S. Ibrahim et al., Ind. J. Het. Chem., 4, 125-130 (1994) describe 1-methylquinolinones. A. Sayed et al., Acta Chim. Acad. Sci. Hung., 94, 131-39 (1977), describes the preparation of 1-alkylquinolinones. M. Abass, Synth. Commun., 30, 2735-57 (2000), describes the preparation of 1-methylquinolinones. WO01/70227, published 27 Sep. 2001, describes 3-heterocyclylquinolinones as GnRH antagonists. WO01/70228, published 27 Sep. 2001, describes 3-phenylquinolinones as GnRH antagonists. WO01/62252, published 30 Aug. 2001, describes 3-pyrrolopyridinyl-quinolinones as tyrosine kinase inhibitors. WO01/29025, published 26 Apr. 2001, describes 3-(2-indolyl)quinolinones as tyrosine kinase inhibitors.
U.S. Pat. No. 5,252,584, issued Oct. 12, 1993, describes 4-hydroxy-quinolinones as NMDA antagonists. K. Ashok et al., Ind. J. Chem., 32B, 786-87 (1993), describe the preparation of 4-hydroxy-quinolinones. E. Mohamed et al., J. Ind. Chem. Soc, 69, 82-4 (1992), describe the preparation of 4-hydroxy-quinolinones. WO92/18483, published 29 Oct. 1992, describes 1-methyl-4-hydroxy-quinolinones as pharmaceuticals. WO01/28993, published 26 Apr. 2001, describes 6-(indazol-2-yl)-thieno[2,3-b]pyridones as kinase inhibitors. M. Rehwald et al., J. Prakt. Chem., 342, 371-78 (2000), describe preparation of heteroaryl pyridinium salts. G. Tenant et al., J. Chem. Soc., Perkin Trans. 1, 827-32 (1999), describe preparation of heterocyclyl-pyridinium salts. K. Gewald et al., Liebigs Ann., 787-91 (1995), describe preparation of heterocyclyl-pyridinium salts. T. El-Emary et al., Pharmazie, 55, 356-58 (2000), describe the preparation of pyrazolo[3,4-b]pyridin-2-ones. S. Naruto, et al., Chem. Pharm. Bull., 30, 3421-23 (1982), describe the preparation of benzofuro[3,2-b]pyridin-2-ones. WO01/62251, published 30 Aug. 2001, describes 3-pyrrolopyridinyl-quinolinones as tyrosine kinase inhibitors. WO01/29025, published 26 Apr. 2001, describes 3-(2-indolyl)quinolinones as tyrosine kinase inhibitors. WO01/28993, published 26 Apr. 2001, describes 3-(2-benzimidazolyl)quinolinones as tyrosine kinase inhibitors. WO01/62252, published 30 Aug. 2001, describes 3-pyrrolopyridinyl-quinolinones. U.S. Pat. No. 5,643,932, issued Jul. 1, 1997, describes thiazoles as superoxide radical inhibitors. A. Doroshenko et al. Chem. Heterocycl. Cmpd., 33, 1177-84 (1998) describes spectral properties of thiazolyl-coumarin derivatives.
However, compounds of the current invention have not been described as inhibitors of cell proliferation or apoptosis such as for the treatment of cancer or stroke.